Great strides have been made in recent years in our understanding of how the cerebral cortex is assembled. The fork head transcription factor FoxG1 is widely expressed within the cortex but loss of this gene results in such severe deficits that only the earliest role of this gene has previously been explored. Over the past five years my laboratory has contributed considerably to our understanding of the role of FoxG1 in development by demonstrating that is plays a role in suppressing the fate of the early cortical cell type (the Cajal Retzius cell) in favor of the production of the principal pyramidal neurons (Hanashima et al., 2004; 2007). Unfortunately even with this effort, the widespread expression of FoxG1 and the early lethality associated with its loss of function has prevented clear understanding of its role in either postmitotic cortical development. To circumvent this impasse, we have generated both gain of function methods, as well as a conditional FoxG1 loss of function allele, which together allows us to examine pyramidal neurons in both these contexts. Our preliminary results support our hypothesis that both the downregulation of FoxG1 as pyramidal neurons enter the multipolar phase followed by upregulation as they leave it are required for pyramidal fate specification and assembly of cortical layers. In this proposal we seek to understand how FoxG1 mediates these critical developmental events by exploring how changes in FoxG1 levels at different points in development are centrally involved in the cellular and molecular cascades needed for proper pyramidal neuron maturation. In particular we will focus on 1) the role of FoxG1 in selecting between radial migration and the multipolar state 2) the negative regulation of Netrin-signaling during the transition from the early to late multipolar phase and 3) the requirement of FoxG1 as a repression to downregulate genes that otherwise would interfere with entry into the cortical plate. Clinical Relevance: Our understanding of the genetic basis for numerous causes of affected mental disorders, such as Rett syndrome and mental retardation, has been limited by good genetic models in mice to study these disorders directly. In humans mutations resulting in partial loss of function of FoxG1 underlies the etiology of both these disorders. Our proposal by exploring the genetic mechanisms by which FoxG1 directs both cortical and adult neurogenesis has the potential to ultimately provide tools for exploring central aspects of these disorders that are at present poorly understood. PUBLIC HEALTH RELEVANCE: In this proposal, we use a novel genetic approach to study the role of a key protein, FoxG1 in the development of the cortex. Mutations in FoxG1 have been implicated as a cause of a number of neurological disorders including mental retardation and Rett Syndrome. Our proposal by studying the function of FoxG1 in contexts that were previously inaccessible will provide insights into how disruption of this gene causes cognitive impairment in humans.